Dr. Drake says: “The basic idea is that radiation, and perhaps other local modalities like cryotherapy, leads to destruction of tumor cells. If they’re destroyed in a way that’s immunogenic or pro-immunogenic, then the dying cells are taken up by resident antigen-presenting cells. These antigen-presenting cells get activated; they traffic to the draining lymph node, if you’re lucky. If they traffic to the draining lymph nodes, and then activate a systemic immune response (T cells), then maybe you can turn a local therapy into a systemic therapy. When that happens, it’s called the abscopal effect. We can demonstrate this in mice fairly readily, but it’s quite hard to demonstrate in humans.

In the literature, it’s not that common. There’s a review paper that reports around 60 total cases in the world that are clearly documented. But if you talk to people who take care of patients, everybody has one or two that they can talk about.”

When you’re diagnosed with prostate cancer, you’re usually offered three options: monitor the cancer to see if it progresses, elect to have your prostate surgically removed, or elect to have the cancer treated with radiation therapy. Radiation is also used after surgery or in the event that the cancer comes back after that initial treatment.

Most of you are familiar with radiation therapy for prostate cancer—how it works, potential side effects, and special considerations. Even if you have not had radiation, chances are you’ve got a friend of relative who has.

This month, however, we’re delving into less often discussed aspects of radiation therapy: the role genomics will play in radiation therapy, why we might consider combining radiation with immunotherapy, the impact imaging has on radiation therapy, and the role radiopharmaceuticals play.

Dr. Robert Bristow of the University of Manchester gives us a sweeping overview of precision radiation therapy—from functional imaging to genomics—as well as a run-down of molecularly-targeted agents.

Dr. Charles Drake of the New York- Presbyterian/Columbia University Medical Center discusses radiation therapy and the elusive but intriguing abscopal effect.

Dr. William Hall of the Medical College of Wisconsin talks to us about the precision radiotherapy movement and how it will revolutionize patient care.

Dr. Daniel Spratt of the University of Michigan Health System talks abouta clinical trial he’s working on with Dr. Felix Feng from the University of California, San Francisco (UCSF) that uses genomics to determine which patients will receive a combination of radiation therapy and Erleada (apalutamide) and which will get a placebo.

From Dr. Ralph Weischelbaum of the University of Chicago we hear about the thinking behind combining radiation therapy with immunotherapeutic agents—with a cautionary note.

Dr. Johannes Czernin from the University of California, Los Angeles (UCLA) talks about a clinical trial he’s running on a radiopharmaceuticalagent—a PSMA targeted lutetium-177. He is looking for patients to join, so if you think you might be a fit, please reach out to him at the email address included at the end of his conversation.

This issue focuses on the interaction between radiation therapy and immunotherapy for prostate cancer. This interaction has been extensively documented in laboratory models where the combined treatment can show benefit even in metastatic prostate cancer.

In the laboratory models, it appears that cancer cells damaged or killed by radiation trigger an immune response. This response can be enhanced by additional agents.

The most promising situation to test this approach is in patients with oligometastatic prostate cancer. These patients have 5 or fewer metastatic lesions that can be targeted by radiation therapy. In this setting, all detectable prostate metastases receive a radiation dose sufficient to treat the cancer.

The hope is that triggering an immune response will enhance the ability of radiation to kill all cancer in the irradiated lesions. There is also a hope that this immune response might suppress the growth of cancer metastases that are present but not radiated because the lesions are too small to be detected. This would act to delay the appearance of new metastatic lesions and possibly extend survival.

There are several unresolved issues in this area of research. First and foremost, immunotherapeutic agents with activity against prostate cancer are of limited effectiveness currently. For example, while the Provenge (sipuleucel-T) vaccine is FDAapproved to treat prostate cancer, it extends survival by only months. Immune checkpoint inhibitors, such as those that target PD1/PD1L, can cause dramatic responses, but they do so in only a small proportion of patients. Nevertheless, prostate cancer immunotherapy is a very active area of investigation with a number of promising concepts at various stages of testing.

Another unresolved issue is when is the best time to administer immunotherapy with regard to radiation treatment—before, during, or after. Radiation dose may also be critical as extensive radiation can dramatically suppress immune system function.

Despite these limitations, this is a research area worthy of investigation. The ultimate goal of cancer treatment is a durable complete remission. As it is unlikely that patients with metastatic cancer will ever be cancer-free, a more reasonable goal is to place remaining cancer cells in a state of dormancy. In laboratory models, immunotherapy is one of the most successful approaches to achieve cancer dormancy.

This month Prostatepedia is talking about radiation therapy.

Here’s the introduction:

Both discuss the future of radiation therapy and offer insight into escalating radiation to the prostate while minimizing dosing to surrounding normal tissue.

Two developments drive this effort. First, improved imaging provides a more detailed view of the cancer’s extent and its localization within the prostate as well as spread to adjacent structures. Dr. Zelefsky outlines MRI imaging’s impact. Dramatic advances in computer power have also allowed radiation oncologists to develop sophisticated treatment planning software. We can calculate with more precision radiation doses to be delivered to the cancer versus to surrounding normal tissue.

Radiation therapists can also focus external beam radiation with greater precision, leading to IMRT and Cyberknife. These techniques use high-energy photons.

We also developed approaches like brachytherapy and proton beam that augment or compete with photon-based treatments. Further progress in intensifying radiation dose may be limited. Drs. Roach and Zelefsky’s comments on these trends are well balanced.

Another trend is to shorten treatment duration. Current treatment plans require eight to nine weeks. Dr. W. Robert Lee outlines two randomized trials that show four to five and a half weeks of treatment is not inferior to eight to nine weeks of treatment. (Increasing daily radiation doses, a strategy called hypofractionation shortens treatment duration.) Shorter treatments are more convenient for patients. Larger doses per session may also reduce costs as radiation oncologists are paid per treatment session.

Stereotactic body radiotherapy (SBRT) is another way to shorten treatment duration. SBRT delivers five treatments over a week and a half. SBRT is at an earlier development stage; we have no randomized trials proving it is better than or equal to standard fractionation or hypofractionation. SBRT has theoretical advantages, as Dr. Zelefsky comments. Early results are promising, but SBRT’s full potential is still being explored.

Dr. Sean McBride’s clinical trial combines SBRT with cutting-edge hormonal therapy in patients with locally advanced disease at very high risk of recurrence after surgery: Gleason 8-10, a PSA >20, extracapsular spread, or cancer invasion into the seminal vesicles or lower part of the bladder.

Disappointingly, current adjuvant hormonal therapy for radiation typically uses LHRH agonists. Xtandi (enzalutimide) and Zytiga (abiraterone) have revolutionized metastatic prostate cancer treatment. Adding both to adjuvant hormonal treatment is persuasive. McBride’s trial uses an LHRH agonist with Zytiga (abitraterone) and a new drug called apalutamide (ARN 509). Apalutamide’s (ARN-509) mechanism of action is similar to Xtandi’s. This combination is frontline treatment for advanced metastatic prostate cancer, but in this trial, it is applied as adjuvant hormonal therapy for locally advanced prostate cancer. This trial promises to revolutionize treatment for locally advanced disease.

I’m very interested in metformin use for prostate cancer. In my clinic, we use metformin when we start hormonal therapy: a randomized trial shows that it reduces metabolic syndrome risk for men on hormonal therapy. Dr. Zelefsky observes that during radiation, patients on metformin have a reduction in distant metastases, risk of dying of prostate cancer, and risk of castrate resistance. This is retrospective data, though; these advantages need to be tested in a randomized controlled trial.